Topical imiquimod - A review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions

Topical imiquimod 5% cream (Aldara(TM)) is an immune response modulator that is indicated for the treatment of external anogenital warts, superficial basal cell carcinoma and actinic keratoses. The cream is applied two to five times per week for varying periods, depending on the indication. Topical imiquimod cream has also been evaluated in the treatment of several other skin conditions. Immunomodulatory therapy with topical imiquimod 5% is an effective option for the approved indications. The drug appears to be relatively well tolerated, with the option of breaks from treatment as required for local skin reactions (which are common). Systemic reactions have been reported. Treatment of human papillomavirus- and UV-associated skin lesions with topical imiquimod offers a noninvasive, tissue-sparing alternative to ablative treatment options. However, well designed trials of the sustained, long-term efficacy and tolerability of topical imiquimod versus those of common treatment approaches including surgery and other topical alternatives are required before the place of the drug in the management of these lesions can be finalised. Nonetheless, while other treatments for anogenital warts, superficial basal cell carcinoma or actinic keratoses are available, the advantages of self treatment linked with the demonstrated efficacy of topical imiquimod offer an attractive alternative for many patients. Pharmacological Properties The topical imidazoquinoline imiquimod stimulates both innate and cell-mediated immune responses to viruses and tumours via an array of molecular events initiated mainly by agonistic actions on toll-like receptor molecules 7 and 8. While most activity occurs at the site of administration, minimal systemic immunomodulation has also been recorded after topical administration. Topical imiquimod has no photosensitising effects and does not aggravate UV-induced damage. Systemic absorption was minimal after application of imiquimod 5% daily for 7 days to healthy volunteers and for up to 16 weeks to patients with anogenital warts. The drug is retained in the skin for prolonged periods, resulting in an apparent elimination half-life of approximate to 1 day. Imiquimod and its active metabolites (S26704 and S27700) are excreted in urine and faeces. Therapeutic Efficacy Several randomised, double-blind trials have consistently demonstrated the short-term superiority of topical imiquimod 5% over placebo in immunocompetent patients with external anogenital warts. Complete clearance of the warts occurred in 40-70% of imiquimod recipients after three-times-weekly or daily administration for 8-16 weeks. Recurrence of anogenital warts occurred in up to 19% of those with complete clearance, over a period of 10-24 weeks of follow-up, resulting in sustained clearance rates of 29-70% with imiquimod. Short-term (<= 16 weeks) clearance rates were similar in men with anogenital warts after treatment with topical imiquimod 5% or fluorouracil 1% three times weekly (58% and 36%) in a double-blind trial published as an abstract. Superiority over placebo was also consistent in the treatment of immunocompetent patients with actinic keratoses in randomised, double-blind trials of topical imiquimod 5% two or three times weekly for 16 weeks, or for 4 weeks followed 4 weeks later by another course if necessary. Complete clearance occurred in 45-57% of imiquimod recipients. Recurrence rates of 8-43% over follow-up of up to 24 months have been reported after two- or three-times-weekly administration over 4-16 weeks. Topical imiquimod 5% was also consistently superior to placebo in the treatment of immunocompetent patients with superficial basal cell carcinoma in randomised, double-blind trials. Complete clearance occurred in 79-87% of imiquimod recipients after five-times-weekly or daily administration for 6 or 12 weeks. Sustained clearance rates taking recurrence into account were not reported for these trials. Less robustly designed trials suggest sustained clearance rates of approximate to 80% at 4 years and 65% at 5 years after imiquimod treatment. Experience with topical imiquimod 5% in the treatment of skin lesions in immunocompromised patients is less extensive. Imiquimod had at least a partial effect (reduction of >50%) on anogenital warts in about half of the HIV-seropositive patients (and was superior to placebo), and on actinic keratoses in about one-third of renal transplant recipients at high risk for skin cancer (similar to placebo), in well designed trials. Tolerability While local skin reactions are common, topical imiquimod 5% is also occasionally associated with systemic adverse events. Systemic events reported in clinical trials (all in <= 10% of recipients) include headache, fatigue, myalgia and nausea. Haemoglobin, white blood cell, absolute neutrophil and platelet counts may be reduced and severe remote skin reactions (erythema multiforme, Stevens-Johnson syndrome, cutaneous lupus erythematosus) have been reported. Underlying immunological disorders may be exacerbated. Local skin reactions (e.g. erythema, excoriation/flaking, erosion, oedema, scabbing/crusting) are very common. Local pruritus in particular was reported in 23-62% of recipients in clinical trials.